Transforming Growth Factor-Beta (TGF-?) has profound immunosuppressive effects on a variety of immune cells. Natural killer (NK) cells are large granular lymphocytes that constitute a vital component of the innate immune system. NK cells produce abundant interferon gamma (IFN-?) to enhance tumor cell recognition and destruction, and to clear viral infection, including herpes simplex oncolytic viruses (OVs) in glioblastoma (GBM) treatment. Due to its complexity, TGF-? signaling has not been fully characterized. It also remains to be determined whether TGF-? itself or TGF-? signaling can be modulated to control NK cell functions in order to better control tumor progression and to enhance OV therapeutic efficacy in GBM. We hypothesize that TGF-? signaling can be further elucidated and modulated in NK cells to better understand cancer progression and enhance cancer treatment. Our goal is to investigate the molecular basis of how TGF-? suppresses NK anti-tumor activity by identifying the elements directly involved in this process, and to study the potential to increase the signaling to improve NK anti-tumor activity, but to decrease NK activity by pre-TGF-? treatment in the context of OV therapy, where NK cells limit OV expansion and therapeutic efficacy. Our proposed studies have a great potential to advance GBM treatment and/or GBM prevention and make us understand more about tumor and virus recognition and destruction. We will test our hypothesis through three Aims: 1) To determine the molecular basis of transcriptional repression of NK cell function by TGF-?; 2) Can we disrupt TGF-? signaling to increase immune responses, and, in turn, to control GBM progression in vivo? 3) To augment TGF-? signaling in NK cells to enhance OV therapy efficacy in GBM. PUBLIC HEALTH RELEVANCE: Glioblastoma (GBM) is the most common and aggressive brain tumor in humans. Although we have researched it for decades, survival time of patients suffering from GBM remains extremely poor. In this application, our first goal is to understand a very important negative signaling initiated by a cytokine, TGF-?. The other goal of this application is to either inhibit or enhance this signaling especially in NK cells at different contexts to treat GBM using our excellent animal models. Eventually, our long-term goal is to apply these studies in patients when we prove they are effective and safe.